In certain applications it is desirable to use electron microscopy to sequence a polymer. Electron microscopy can theoretically be used, for example, to sequence bases of a nucleic acid, such as the bases of a strand of deoxyribonucleic acid (DNA). The polymer is labeled at its structural units and stretched onto a substrate. An electron microscope is then used to scan the polymer and thereby generate an image, which can be analyzed to identify the labels. Based on the correspondence of the label types with the structural unit types to which they bond, the polymer can be sequenced.
Using conventional transmission electron microscopy (TEM) for sequencing may, however, suffer from an undesirably low ratio of signal from the labels to noise from the substrate or other causes. Images generated by electron microscopy may also not be optimally focused at every portion of a polymer strand, which can detract from the ability to locate and identify the labels. Moreover, performing conventional transmission electron microscopy may take an undesirably long time for polymer sequencing. The throughput may be especially low for sequencing long polymers, such as a full human genome, in any practical amount of time.
Thus, it is desirable to provide electron microscopy with a signal-to-noise ratio that is sufficiently good for polymer sequencing. It is also desirable for the electron microscope images to be focused at every part of a polymer strand being examined. Moreover, it is desirable for the electron microscopy to have a substantially high throughput to sequence the polymer sufficiently fast to be practical.